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Clazosentan Found to Decrease Severe Post-TBI Hypoperfusion in Animal Model: Next Step: Filing for Human Trial

Since graduate school, Christian Kreipke, PhD, has puzzled over the events that unfold in traumatic brain injury (TBI). Now, little more than a decade later the neuroscientist from Wayne State University may have come up with a treatment that works to prevent some of the brain damage.

His findings, released in abstract form online in February, will be discussed in greater detail at the upcoming AAN annual meeting in New Orleans in April.

Dr. Kreipke, an assistant professor of anatomy and cell biology, realized early on in his studies that one of the core features of TBI is a significant reduction in blood flow. Restoring that flow, he thought, might reduce the effects of the initial damage.

He had shown in previous work that endothelin-1 plays a major role in triggering hypoperfusion. He and his colleagues studied the endothelin-1 receptor on the heels of injury and found that it was upregulated within hours of the injury and was still working overtime up to two days later. If they could block that upregulation, Dr. Kreipke thought it might be possible to prevent hypoperfusion and save the brain from damage.

According to the results from the lab's latest study, it worked. Dr. Kreipke and his colleagues used a rodent model of diffuse traumatic brain injury (weight accelerated impact) and administered intravenously a dose of the selective endothelin-1 receptor (ETrA) antagonist, clazosentan, five different times post-TBI: 30 minutes, two hours, four hours, 12 hours, and 24 hours. They measured cerebral blood flow throughout the study and 20 days after the treatment they worked the animals on several mazes to see whether there was an improvement in function.

Dr. Kreipke reported there was a marked decrease in the severity of post-TBI hypoperfusion in the animals that received clazosentan at 30 minutes, two hours, and four hours. At 12 hours out, the effects were variable. Some animals got better but some did worse. The group that received the IV treatment at two and 20 hours had the best outcomes.

“We think that this tells us that we could use a selective ETrA antagonist to prevent the deleterious effects of TBI,” said Dr. Kreipke. “Our results suggest that there is probably a ‘window of opportunity’ to ensure the best outcomes.”

While the scientist said that problems with blood flow seems like an obvious problem in TBI, there have been no drug trials to stop the decrease in blood flow following brain trauma. Clazosentan was tested in a phase 3 study on subarachnoid hemorrhage but it had mixed results. (See “Clazosentan Prevents Secondary Vasospasm But Fails to Reduce Stroke Mortality,” a report from the American Stroke Association International Stroke Conference, on page 4 of this issue.

The Wayne State scientists tested the animals three weeks after injury to see whether there were drug-related changes in spatial learning and memory retention. Testing in a radial maze with eight equidistant arms allows the scientists to see if the animals can remember the location of food. When the drug was given post-TBI at two hours, the animal's performance up to 20 days later returned to their baseline values. Animals that had not been treated with the ETrA antagonist continued to make multiple mistakes up and down the arms of the maze.

“They don't even seem to know what they are doing there,” he said. While the animals do show improvements over time they never return to their baseline ability to find food quickly and efficiently in the maze.

The scientists say that they are modeling moderate head injury. The group has just filed to the FDA for an Investigational New Drug Application to test the ETrA antagonist in humans. Part of their research funding comes from the Department of Defense.

“What is most alluring is that this drug, clazosentan, is very specific to this problem of hypoperfusion and very specific to the brain,” said Dr. Kreipke. “We use very low doses and it is a really focused treatment. The hope would be to have an IV drug we could deliver quickly.”

He said that there is also evidence from his laboratory work that the drug might have another role beyond blood flow. His team is finding that the drug has effects in models of diffuse axonal injury.

Dr. Kreipke said that it was surprising that endothelin receptors are even in neurons. His work and others has led to the finding that in early development these receptors are critical for axon guidance. In knock-out animals without these receptors the axons failed to cross the midline of the brain. Dr. Kreipke said that there is evidence that these receptors revert to a developmental state following stroke and severe head trauma.

During his talk at the AAN he will focus on the “window of opportunity,” he said. They have also developed a more refined way of measuring blood flow.

EXPERT COMMENTS

J. Paul Muizelaar, MD, the Julian R. Youmans Chair of Neurosurgery at University of California, Davis, knows Dr. Kreipke's animal work well. He studied the role of ischemia after severe head injury and was excited to see that he used a method to stop the hypoperfusion and that it made a difference in outcome for the animals.

He said that about 40 percent of TBI patients have some ischemia following the injury and it could continue over the course of a few days. “They were doing things that you would not expect them to do,” said Dr. Muizelaar. “This could change the management of traumatic brain injury. It is quite spectacular. This is the first time ischemia has been treated in experimental animals with head injury.”

He added that it is necessary to find a drug that crosses the blood brain barrier and this meets that criterion. “What is impressive is that it changes behavioral outcomes. It is very promising,” he said.

Clazosentan has already been used in humans, and proven safe, he added. “Nothing before has helped with head injury, not even in animals,” said Dr. Muizelaar.

“We know that the role of ischemia following severe head injury is under-reported. It's very difficult to measure blood flow all the time,” he continued. “I think the next step should be a dose escalation study in patien`ts and then a randomized double-blind trial.”